As part of LMC's work on the elucidation of the structure and function of neurotransmitter systems in the mammalian central nervous system (CNS) and the molecular mechanism of action of CNS active drugs, theoretical approaches to the study of the interaction of selective agonists for the delta opioid receptor were employed. An LMC delta opioid recognition pharmacophore was designed and two well-recognized selective delta agonists, SNC80 and oxymorphindole, were examined. We found, both from pharmacophoric analysis and from applicable molecular structure- biological analysis, that these prototypic delta agonists most likely interact with the delta opioid receptor at different sites or in a different orientation, and this predicts that their SAR should be dissimilar. In a second study, the effect of an N- benzyl substituent on the in vitro, and in vivo activity of (-)- and (+)-N-normetazocines, (-)- and (+)-N-normorphinans, N- norketobemidones, and (-)-N-nor-4,5-epoxymorphinans was collaboratively studied with the Drug Evaluation Committee, CPDD, and it was found that an N-benzyl moiety in these prototypic opioids tended to prevent interaction with opioid receptors and promote interaction with sigma binding sites. Neither the size of a benzylic substituent (larger and smaller substituents interact well with opioid receptors), nor its aromaticity, or electrophilicity, was found to be responsible for preventing interaction with opioid receptors, implying that the N-benzyl substituent was unable to allow a necessary and precise fit to a three-dimensional pocket in the mu or kappa opioid.